Title : X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate
receptor
Abstract :
- Ionotropic glutamate receptors mediate most excitatory neurotransmission in the central nervous system and function by opening a transmembrane ion channel upon binding of glutamate
- Despite their crucial role in neurobiology, the architecture and atomic structure of an intact ionotropic glutamate receptor are unknown
- Here we report the crystal structure of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive, homotetrameric, rat GluA2 receptor at 3 .6 A resolution in complex with a competitive antagonist
- The receptor harbours an overall axis of two-fold symmetry with the extracellular domains organized as pairs of local dimers and with the ion channel domain exhibiting four-fold symmetry
- A symmetry mismatch between the extracellular and ion channel domains is mediated by two pairs of conformationally distinct subunits , A/C and B/D
- Therefore, the stereochemical manner in which the A/C subunits are coupled to the ion channel gate is different from the B/D subunits
- Guided by the GluA2 structure and site-directed cysteine mutagenesis, we suggest that GluN1 and GluN2A NMDA ( N-methyl-d-aspartate ) receptors have a similar architecture, with subunits arranged in a 1- 2-1-2 pattern
- We exploit the GluA2 structure to develop mechanisms of ion channel activation, desensitization and inhibition by non-competitive antagonists and pore blockers